Obesity is characterized by excessive body fat accumulation and is, therefore, a major risk factor for the development of physical and mental disorders [1]. Humans and other organisms have evolved metabolic pathways which control lipid homeostasis. Among numerous signaling pathways adipogenesis is regulated by peroxisome proliferator-activated receptor gamma (PPARg) cascades which are modulated by ligands of PPARg, such as endogenous polyunsaturated fatty acids but also environmental compounds.
Phthalate di(2-ethylhexyl) phthalate (DEHP) and its substitute cyclohexanoate cyclohexane-1,2-dicarboxylic acid diisononyl ester (DINCH) which are widely used as plasticizers are known for their effect in impaired health [2, 3]. Previous surface plasmon resonance (SPR) data and studies on adipocytes already suggest a direct binding of MEHP to PPARg but sufficient data for MINCH are still missing [4, 5]. Moreover, a detailed structural understanding of how these plasticizers interact with PPARg and, as a consequence, affect human health is lacking until now. To answer this, we structurally characterize the molecular mode by which plasticizers target PPARg and compared their binding to known endogenous, and synthetic agonists of PPARg. Using crystallography, we identified the binding site of MEHP and MINCH in the human PPARg and described the conformational changes of PPARg and its PPARg-RXR interaction surface upon ligand binding, characterizing these compounds as PPARg agonists.
The Deutsche Forschungsgemeinschaft (CRC1052) is greatly acknowledged for funding. We thank the MX Laboratory at the Helmholtz Zentrum Berlin (BESSY II) and the EMBL beamlines of the DESY synchrotron in Hamburg for synchrotron beamtime.